Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG

Luo，Pingping1,2; Wang，Fei3; Wong，Nai Kei4; Lv，Yi2; Li，Xinxin5; Li，Mianhuan1,2; Tipoe，George L.6; So，Kwok Fai7; Xu，Aimin8; Chen，Shuaiyin9; Xiao，Jia1,2,6; Wang，Hua10

2020

10.1016/j.jcmgh.2019.09.002

Cellular and Molecular Gastroenterology and Hepatology   影响因子和分区

2352-345X

2352-345X

Background & Aims: Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood. Methods: ALD-associated liver injury were induced in TLR2 knockout (TLR2), TLR3, TLR2 bone marrow transplanted (BMT), TLR3 BMT, IL-10 mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl injection to evaluate their pathogenic roles in ALD. Results: We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG's actions. Conclusions: Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production.

Alcoholic Liver Disease EGCG Kupffer Cell Toll-like Receptor

SCI

英语

其他

Scientific Cultivation Grant of Jinan University[21617444]

Gastroenterology & Hepatology

Gastroenterology & Hepatology

WOS:000503005500009

ELSEVIER INC

2-s2.0-85075560628

Scopus

1.Clinical Medicine Research Institute,First Affiliated Hospital of Jinan University,Guangzhou,China
2.Laboratory of Neuroendocrinology,School of Biological Sciences,Fujian Normal University,Fuzhou,China
3.Digestive Disease Institute of Tongji Hospital,Tongji University School of Medicine,Shanghai,China
4.State Key Discipline of Infectious Diseases,Department of Infectious Diseases,Shenzhen Third People's Hospital,Southern University of Science and Technology,Shenzhen,China
5.Research Center for Clinical Sciences,Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China
6.School of Biomedical Sciences,Li Ka Shing Faculty of Medicine,University of Hong Kong,Hong Kong
7.GMH Institute of CNS Regeneration,Guangdong Medical Key Laboratory of Brain Function and Diseases,Jinan University,Guangzhou,China
8.Department of Medicine,Li Ka Shing Faculty of Medicine,University of Hong Kong,Hong Kong
9.Department of Epidemiology,College of Public Health,Zhengzhou University,Zhengzhou,China
10.Department of Oncology,First Affiliated Hospital,Institute for Liver Diseases of Anhui Medical University,Hefei,China

Luo，Pingping,Wang，Fei,Wong，Nai Kei,et al. Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG[J]. Cellular and Molecular Gastroenterology and Hepatology,2020,9(1):145-160.

Luo，Pingping.,Wang，Fei.,Wong，Nai Kei.,Lv，Yi.,Li，Xinxin.,...&Wang，Hua.(2020).Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG.Cellular and Molecular Gastroenterology and Hepatology,9(1),145-160.

Luo，Pingping,et al."Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG".Cellular and Molecular Gastroenterology and Hepatology 9.1(2020):145-160.